tbuckley/cabot-search huggingface dataset:
Abstract 200: Microtube Array Membrane-Hollow Fiber Assay (MTAM-HFA): A combination of immunocheckpoint blocker (ICBs) and secondary drug anti-cancer drug screening system with significant clinical value propositions for personalized medicine and pre-clinical drug development
Authors: Wan-Ting Huang, Chee Ho Chew, Amanda Chen, Kang-Yuan Lee, Hsing-Lun Lee, Po-Hao Feng, Jeng-Fong Chiou, Kuan-Chou Lin, Po-Li Wei, Chien-Chung Chen
Journal: Cancer Research (2022)

Abstract Despite modern advances in technology, significant challenges still plague the development of new cancer drugs and cancer care. To address these issue, we are introducing our novel platform technology- Microtube Array Membrane-Hollow Fiber Assay (MTAM-HFA) that is based on combination of the patented MTAM membrane with unique microstructures; replacing the role of traditional hollow fibers enabled the entire HFA assay to be significantly improved in terms of clinical relevance, accuracy, reliability and cost resulting in unprecedented value propositions as an anti-cancer drug screening platform. In the current work, we have clinically demonstrated in several cases where the MTAM-HFA system is capable of accurately predicting clinical response in several Cancers-Lung, Breast and Colon cancers; with unprecedented flexibility of being screened against multiple drug class (including anti-PD1/PDL1) in monotherapy and combination therapy settings. Despite being a phenotypic based assay, the test cycle of MTAM-HFA is only 7-10 days while maintaining a very low cost of up to 60% savings when compared to traditional models such as Patient Derived Xenografts (PDX). When screening ICBs, without the need to use Genetically Engineered Mice (GEM) translates to a cost savings of 98% just for the animal model alone. The combined value proposition of MTAM-HFA makes is a suitable system fulfilling the needs of multiple stakeholders. Citation Format: Wan-Ting Huang, Chee Ho Chew, Amanda Chen, Kang-Yuan Lee, Hsing-Lun Lee, Po-Hao Feng, Jeng-Fong Chiou, Kuan-Chou Lin, Po-Li Wei, Chien-Chung Chen. Microtube Array Membrane-Hollow Fiber Assay (MTAM-HFA): A combination of immunocheckpoint blocker (ICBs) and secondary drug anti-cancer drug screening system with significant clinical value propositions for personalized medicine and pre-clinical drug development [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 200.
The Role of Health Care Systems in Bolstering the Social Safety Net to Address Health Inequities in the Wake of the COVID-19 Pandemic
Authors: Rita Hamad, Sandro Galea
Journal: JAMA (2022)

This Viewpoint discusses how relying almost exclusively on health care systems to address overall health in the US is problematic, noting that safety net programs and other social policies can serve as powerful population-level interventions that can affect long-standing health disparities.
Abstract 2583: Utilization of a novel double knock-in humanized mouse model to evaluate the efficacy of ipilimumab and pembrolizumab against EMT-6 mammary carcinoma tumors
Authors: Murray Stackhouse, Mariah Kuta, Joseph Kolb, Sydney Scatigno, Amber Blackwell, Chassidy Hall, Christopher Dowdy, Payel Sil, Diana Gietl, Steve Festin, Paula L. Miliani De Marval
Journal: Cancer Research (2022)

Abstract The cancer immunotherapy field has seen an increasing demand for identifying and characterizing pre-clinical models to evaluate the efficacy of the checkpoint inhibitors such as, ipilimumab and pembrolizumab. PBMC- or CD34-humanized mouse models are invaluable tools to assess effector functions of human T-cells to immune check point inhibitors (ICI). However, these models offer limited understanding of the overall potential therapeutic activity as they lack a complete repertoire of human immune cells required to elicit a full immune response. Thus, the development of multigenic humanized knock-in models provide a unique approach to evaluate the efficacy of ICI specific for human cancer targets in a fully immunocompetent organism. Here we describe the response of the EMT-6 murine breast cancer tumor model to ipilimumab and pembrolizumab in a novel hPDCD1/hCTLA4-KI double knock-in humanized BALB/c mouse model. EMT-6 tumors were implanted subcutaneously in the flank of hPDCD1/hCTLA4-KI mice. Three days post-implant we initiated treatment with ipilimumab or pembrolizumab alone and in combination. We observed significant ipilimumab anti-tumor activity, whereas pembrolizumab did not show efficacy despite effective T-cell PD-1 blockade. Unexpectedly, sudden respiratory distress occurred in animals receiving the 4th dose of combination therapy and the treatment was discontinued. To assess the immune phenotypic profiles in response to ipilimumab and/or pembrolizumab therapies, we performed multi-parameter flow cytometry analysis of peripheral blood, spleens and tumors. Additionally, we performed histopathological evaluation of lung tissues to assess potential neutrophil infiltration-mediated anaphylaxis in the mice treated with the combination treatment. The preliminary results highlight the value of the hPDCD1/hCTLA4-KI double knock-in humanized Balb/c model as a tool to evaluate human-specific immune-checkpoint based modalities. These models represent some of the difficulties faced in treating refractory tumors as well as reproducing some of the adverse effects seen in the clinic. Citation Format: Murray Stackhouse, Mariah Kuta, Joseph Kolb, Sydney Scatigno, Amber Blackwell, Chassidy Hall, Christopher Dowdy, Payel Sil, Diana Gietl, Steve Festin, Paula L. Miliani De Marval. Utilization of a novel double knock-in humanized mouse model to evaluate the efficacy of ipilimumab and pembrolizumab against EMT-6 mammary carcinoma tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2583.
Abstract 137: Abrogating therapy induced senescence driven bone loss to improve quality of life
Authors: Ganesh Kumar Raut, Zhangting Yao, Tom Cole, Xainmin Luo, Qihao Ren, Sheila A. Stewart
Journal: Cancer Research (2022)

Abstract Despite the central role chemotherapy plays in prolonging survival, the toxicities associated with its use can negatively impact quality of life and in some cases, be so severe that patients forego further life preserving treatments. Therefore, it is critical that we understand the mechanisms that drive these toxicities and develop approaches to mitigate their severity. Recently we demonstrated that chemotherapy-induced senescence drives bone loss by both limiting mineralization of new bone and increasing bone resorption. To establish whether senescent bone resident cells or systemic responses to chemotherapy drove therapy-induced bone loss, we used a vossicle model in which neonatal vertebral bones (L4 and L5) were transplanted from 4-day old wildtype or INKATTAC pups (allow to selectively kill senescent cells) into wildtype or INKATTAC adult mice. Using this approach, we found that the elimination of senescent cells in donor vossicles protects from chemotherapy-induced bone loss, indicating that senescent bone resident cells are responsible for therapy-induced bone loss. To understand the mechanism(s) that contributed to therapy-induced bone loss, we used scRNA-seq to determine which bone resident cells underwent senescence in response to chemotherapy and how their gene expression was impacted. Using this approach, we found that adipocytes, fibroblast, chondrocytes and osteoblasts underwent senescence as evidenced by expression of p16, p21 and loss of Mki67 and displayed evidence of a senescence associated secretory phenotype (SASP), which we postulate contributes to therapy-induced bone loss. Collectively, our data indicated that chemotherapy causes bone loss via senescence and can be protected by eliminating senescent cells. Citation Format: Ganesh Kumar Raut, Zhangting Yao, Tom Cole, Xainmin Luo, Qihao Ren, Sheila A. Stewart. Abrogating therapy induced senescence driven bone loss to improve quality of life [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 137.
Abstract 6401: PSMA-positive membranes secreted from prostate cancer cells have potency to transform vascular endothelial cells into an angiogenic state
Authors: RYUTA WATANABE, MASASHI MAEKAWA, TAKASHI KIYOI, MIE KURATA, NORIYOSHI MIURA, TADAHIKO KIKUGAWA, SHIGEKI HIGASHIYAMA, TAKASHI SAIKA
Journal: Cancer Research (2022)

Abstract Introduction &amp; objectives: Prostate-specific membrane antigen (PSMA) is highly expressed in poorly differentiated, metastatic, and castration-resistant prostate cancers. Recently, 68Ga-PSMA Positron Emission Tomography/Computed Tomography (PET/CT) has been successfully developed as an effective diagnostic tool for prostate cancer. However, the pathophysiological functions of PSMA in prostate tumors remain unclear. Materials &amp; methods: We examined the protein expression of PSMA in tumor endothelial cells in human prostate tumors by immunohistochemistry. Prostate cancer tissues were resected by robotic surgery in 2019 at Ehime University from patients with prostate cancer. In vitro, we prepared conditioned medium derived from a PSMA-positive human prostate cancer cell line, LNCaP, cultured on collagen I gels. We then examined PSMA expression in human umbilical vascular endothelial cells (HUVECs) cultured with the conditioned medium. We assessed angiogenic activities by treatment of HUVECs with LNCaP-derived conditioned medium using a tube formation assay that mimics angiogenesis. Results: Immunohistochemical positivity of PSMA and CD31, a marker of endothelial cells, and PSMA-expressing tumor endothelial cells were observed in four of 33 prostate cancer patients (12.1%). We also found that the 10,000 × g pellet fraction of the LNCaP-derived conditioned medium containing PSMA-positive membranes, including microvesicles, transformed HUVECs from “PSMA-negative” to “PSMA-positive.” Mass spectrometry revealed that the fraction contained an important growth factor. Furthermore, treating HUVECs with the 10,000 × g pellet fraction of the LNCaP-derived conditioned medium significantly promoted tube formation, mimicking angiogenesis in a PSMA-dependent manner. Conclusions: Our findings revealed the existence of PSMA-positive tumor endothelial cells in human prostate tumors, which enhances tumor angiogenesis in prostate cancer tissues. The endocytic process of the PSMA-positive microvesicles in normal endothelial cells may be an attractive target to develop novel anti-angiogenic drugs, which could inhibit transformation of normal endothelial cells to tumor endothelial cells (Watanabe et al., The Prostate. 2021. in press). Citation Format: RYUTA WATANABE, MASASHI MAEKAWA, TAKASHI KIYOI, MIE KURATA, NORIYOSHI MIURA, TADAHIKO KIKUGAWA, SHIGEKI HIGASHIYAMA, TAKASHI SAIKA. PSMA-positive membranes secreted from prostate cancer cells have potency to transform vascular endothelial cells into an angiogenic state [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6401.
Abstract 3768: Epigenetic dysregulation from chromosomal transit in micronuclei
Authors: Albert S. Agustinus, Ramya Raviram, Bhargavi Dameracharla, Jens Luebeck, Stephanie Stransky, Lorenzo Scipioni, Robert M. Myers, Melody Di Bona, Mercedes Duran, Britta Weigelt, Shira Yomtoubian, Eleonore Toufektchan, Paul S. Mischel, Vivek Mittal, Sohrab Shah, John Maciejowski, Enrico Gratton, Peter Ly, Mathieu F. Bakhoum, Dan Landau, Vineet Bafna, Simone Sidoli, Yael David, Samuel F. Bakhoum
Journal: Cancer Research (2022)

Abstract Chromosomal instability (CIN) and epigenetic alterations are characteristics of advanced and metastatic cancers, yet whether they are mechanistically linked is unknown. Here we show that missegregation of mitotic chromosomes, their sequestration in micronuclei, and subsequent micronuclear envelope rupture profoundly disrupt normal histone post-translational modifications (PTMs), a phenomenon conserved across humans and mice as well as cancer and nontransformed cells. Some of the changes to histone PTMs occur due to micronuclear envelope rupture whereas others are inherited from mitotic abnormalities prior to micronucleus formation. Using orthogonal techniques, we show that micronuclei exhibit extensive differences in chromatin accessibility with a strong positional bias between promoters and distal or intergenic regions. Finally, we show that inducing CIN engenders widespread epigenetic dysregulation and that chromosomes which transit in micronuclei experience durable abnormalities in their accessibility long after they have been reincorporated into the primary nucleus. Thus, in addition to genomic copy number alterations, CIN can serve as a vehicle for epigenetic reprogramming and heterogeneity in cancer. Citation Format: Albert S. Agustinus, Ramya Raviram, Bhargavi Dameracharla, Jens Luebeck, Stephanie Stransky, Lorenzo Scipioni, Robert M. Myers, Melody Di Bona, Mercedes Duran, Britta Weigelt, Shira Yomtoubian, Eleonore Toufektchan, Paul S. Mischel, Vivek Mittal, Sohrab Shah, John Maciejowski, Enrico Gratton, Peter Ly, Mathieu F. Bakhoum, Dan Landau, Vineet Bafna, Simone Sidoli, Yael David, Samuel F. Bakhoum. Epigenetic dysregulation from chromosomal transit in micronuclei [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3768.
Abstract 3666: Dietary potassium and risk of colorectal cancer: Findings from the Singapore Chinese Cohort Study
Authors: Hung N. Luu, Pedram Paragomi, Yi-Chuan Yu, Aizhen Jin, Renwei Wang, Robert E. Schoen, Woon-Puay Koh, Jian-Min Yuan
Journal: Cancer Research (2022)

Abstract Background: Colorectal cancer (CRC) is a commonly diagnosed subtype of cancer with a high mortality rate. Potassium is a necessary trace element in the human boy and is derived mainly from diet. Prior studies found high intakes of potassium was inversely associated with colorectal cancer occurrence in Western population. No such effort has been made in Asian population. Methods: We examined the associations for dietary potassium with the risk of CRC in the Singapore Chinese Health Study (SCHS), a population-based prospective cohort study that includes 61,321 Chinese men and women in Singapore who were 45-74 years of age at baseline. Daily intake of potassium was derived from the self-reported intake of pre-defined food items using a validated semi-quantitative food frequency questionnaire (FFQ) at baseline according to the Singapore Food Composition Table. Cox proportional hazard regression model was used to estimate the hazard ratios (HRs) and respective 95% confidence intervals (CIs) for CRC associated with higher quartile of potassium compared with the lowest quartile with adjustment for potential confounders. Results: After an average of 17.5 years of follow-up, 2,140 participants developed CRC. Dietary potassium was inversely associated with CRC risk. The multivariable-adjusted HR of CRC for the highest relative to the lowest quarter of daily potassium intake was 0.85 (95% CI 0.75-0.96, Ptrend=0.03). The inverse association between high intake of potassium and CRC risk was more apparent among participants with body mass index (BMI) ≥ 23 kg/m2 (HRQ4vsQ1=0.75, 95% CI: 0.63-0.89; Ptrend=0.003) and those with history of type 2 diabetes (HRQ4vsQ1=0.65, 95% CI: 0.42-1.00; Ptrend=0.36). Conclusions: In a large population-based prospective cohort study of more than 61,000 Chinese Singaporeans, we found inverse associations between dietary potassium intake and CRC risk. Future studies are warranted to elucidate the biological mechanism for the protective effect of potassium on the development of CRC. Citation Format: Hung N. Luu, Pedram Paragomi, Yi-Chuan Yu, Aizhen Jin, Renwei Wang, Robert E. Schoen, Woon-Puay Koh, Jian-Min Yuan. Dietary potassium and risk of colorectal cancer: Findings from the Singapore Chinese Cohort Study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3666.
Abstract 5728: A druggable FOXA1-glucocorticoid receptor transcriptional axis drives tumor growth in NSCLC
Authors: Madeline Dorso
Journal: Cancer Research (2022)

Abstract FOXA1 is a pioneer factor that is essential to steroid receptor function in hormone-dependent adenocarcinomas, including breast and prostate cancer. FOXA1 expression is also observed in other tumors of epithelial lineage such as non-small cell lung cancer (NSCLC), but whether and how it is required for tumor growth in these contexts is not known. Analyzing data from genome-scaled pooled loss-of-function screens, we identified and validated a subset of NSCLC cell lines with reduced cellular fitness following FOXA1 knockout. We performed a rapid immunoprecipitation and mass spectrometry of endogenous proteins (RIME) screen to nominate candidate factors that may cooperate with FOXA1 to mediate oncogenic transcription programs. This screen revealed a chromatin-localized interaction between FOXA1 and the glucocorticoid receptor (GR). Depletion of GR expression using shRNA or CRISPR/Cas9 suppressed the proliferation of FOXA1-dependent, but not FOXA1-independent NSCLC models, suggesting GR specifically contributes to tumor growth in the FOXA1-dependent context. To assess the potential therapeutic utility of targeting the FOXA1-GR signaling axis, we employed two structurally distinct ligand antagonists of GR from ORIC Pharmaceuticals: ORIC-101, a steroidal antagonist, and OP-4954, a non-steroidal antagonist. Both antagonists inhibited dexamethasone stimulated GR-transactivation of a glucocorticoid response element (GRE)-luciferase reporter with equal potency. However, proliferation and colony formation of the FOXA1/GR-dependent NSCLC cells were only inhibited upon treatment with ORIC-101, and not OP-4954. Gene expression analysis uncovered a discrete set of GR target genes, including SFTPB, TRAF4 and SGK1, whose expression was reduced by ORIC-101 but unaffected or even induced by OP-4954. The specific inhibition of GR target gene expression and attendant induction of apoptosis by ORIC-101 suggest a hierarchy of GR targets relevant to the FOXA1/GR-growth program in NSCLC. Finally, we evaluated the in vivo therapeutic potential of ORIC-101 using NSCLC xenografts and found that single-agent ORIC-101 exhibited potent antitumor effects in these models. Taken together, these data establish a model of FOXA1-GR-dependent tumor growth amongst a subset of NSCLCs and demonstrate that effective blockade of this complex is a rational therapeutic avenue to be explored in the clinic. Citation Format: Madeline Dorso. A druggable FOXA1-glucocorticoid receptor transcriptional axis drives tumor growth in NSCLC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5728.
Abstract 360: Methyl-cantharidimide (MCA) can induce apoptosis by activating UNC5B-Netrin-1-DAPK pathway in hepatocellular carcinoma
Authors: Yi-Dong Li, Yong Mao, Xing-Duo Dong, Zi-Ning Lei, Yuqi Yang, Lizhu Lin, Dong-Hua Yang, Zhe-Sheng Chen
Journal: Cancer Research (2022)

Abstract In this study, we investigated the underlying mechanism of action of methyl-cantharidimide (MCA), a cantharidin (CTD) analog, as an anticancer drug, in resistant cancer cells overexpressing either ABCB1 or ABCG2 and in cisplatin-resistant cancer cells. The results indicated that: (i) MCA was efficacious in the ABCB1-overexpressing cell line, KB-C2, the ABCG2-overexpressing cell line, NCI-H460/MX20 and in the cisplatin resistant cancer cell lines, KCP-4 and BEL-7404/CP20; (ii) MCA induced apoptosis in both BEL-7404 and BEL-7404/CP20 cancer cells and arrested both BEL-7404 and BEL-7404/CP20 cancer cells in the G0/G1 phase of the cell cycle; (iii) MCA upregulated the expression level of the protein, unc-5 netrin receptor B (UNC5B) in HepG2 and BEL-7404 cancer cells. (iv) MCA can activate UNC5B-Netrin-1-DAPK apoptosis pathway in hepatocellular carcinoma cells. Overall, our results indicated that MCA's efficacy in multiple cancer cell lines is due to the activation of UNC5B-Netrin-1-DAPK apoptosis pathway and cell cycle arrest in the G0/G1 phase. Citation Format: Yi-Dong Li, Yong Mao, Xing-Duo Dong, Zi-Ning Lei, Yuqi Yang, Lizhu Lin, Dong-Hua Yang, Zhe-Sheng Chen. Methyl-cantharidimide (MCA) can induce apoptosis by activating UNC5B-Netrin-1-DAPK pathway in hepatocellular carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 360.
Abstract 803: Identifying a RAD18/UBC13-dependent mechanism of replication fork recovery to modulate chemoresponse in BRCA1-deficient cancers
Authors: Emily Cybulla, Jessica Jackson, Stephanie Tirman, Annabel Quinet, Delphine Lemacon, Alessandro Vindigni
Journal: Cancer Research (2022)

Abstract Mutations in the breast cancer susceptibility genes BRCA1 and BRCA2 are associated with an increased lifetime risk of breast and ovarian cancers. While the BRCA proteins play a well-established role in double-stranded DNA break repair, recent studies have revealed an emerging role of BRCA1/2 in replication stress response. While replication forks are extensively degraded by nucleases in BRCA-deficient cancer cells, activation of specialized fork recovery mechanisms enables resumption of DNA synthesis and promotes cell survival. My project aims to determine this fork recovery mechanism in BRCA1-deficient cells and to identify potential recovery factors that can be targeted to improve chemotherapeutic response in BRCA1-mutated breast and ovarian cancers. To monitor perturbations in replication fork dynamics on a genome-wide scale, we utilize a DNA fiber assay technique measuring rates of fork recovery and replication fork degradation. In parallel, electron microscopy analysis allows direct visualization of replication fork intermediates. Cell survival assays are employed to test how loss of fork recovery factors impacts cell proliferation and chemotherapeutic response in BRCA1-deficient cells. Our results reveal that RAD18 and UBC13, which catalyze ubiquitination of Proliferating Cellular Nuclear Antigen (PCNA), promote fork recovery in BRCA1-deficient, but not BRCA2-deficient, cancer cells. Previous work has also shown that PCNA polyubiquitination by UBC13 is important for reversed fork formation in BRCA-proficient cells. However, our findings show that extensive degradation of reversed fork substrates still occurs in BRCA1-deficient cells lacking RAD18 or UBC13, indicating that PCNA polyubiquitination is not essential for fork reversal in this genetic background. In addition, loss of RAD18 in BRCA1-deficient cells significantly slows cell proliferation, and UBC13 inhibition further sensitizes cells lacking BRCA1 to the replication stress inducer Hydroxyurea (HU). Based on our findings, we hypothesize that RAD18, UBC13, and PCNA ubiquitination may represent novel targets to improve chemoresponse in BRCA1-deficient cancers that rely on fork recovery mechanisms for survival. Citation Format: Emily Cybulla, Jessica Jackson, Stephanie Tirman, Annabel Quinet, Delphine Lemacon, Alessandro Vindigni. Identifying a RAD18/UBC13-dependent mechanism of replication fork recovery to modulate chemoresponse in BRCA1-deficient cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 803.